4-Oxa phenyl-substituted PGE compounds

ABSTRACT

This invention is a group of 3-oxa and 4-oxa phenyl-substituted PGE type, PGF type, PGA type and PGB type compounds, and processes for making those. These compounds are useful for a variety of pharmacological purposes, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement at term, and wound healing.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a division of application Ser. No. 459,759, filed Apr. 11, 1974 now U.S. Pat. No. 3,931,289, which is a continuation of my copending application Ser. No. 185,448, filed Sept. 30, 1971, which was a continuation-in-part of my copending application Ser. No. 103,338 filed Dec. 31, 1970, and now abandoned.

DESCRIPTION OF THE INVENTION

This invention relates to novel compositions of matter, to novel methods for producing them, and to novel chemical intermediates useful in those processes. Particularly, this invention relates to certain novel analogs of prostaglandins E₁, E₂, F₁.sub.α, F₁.sub.β, F₂.sub.α, F₂.sub.β, A₁, A₂, B₁, B₂, and the dihydro derivatives of the PG₁ compounds. These novel analogs each have an oxa oxygen (--O--) in place of the methylene (--CH₂ --) moiety at the 3-position or at the 4-position of the prostanoic acid structure and also have a benzene ring as part of the C-13 to C-20 chain of the prostanoic acid.

The essential material for this application, including the background of the invention, the disclosure of the invention, and the description of the preferred embodiments, including Preparations and Examples, is incorporated by reference from U.S. Pat. No. 3,931,289, columns 1-101, inclusive, under the provisions of M.P.E.P. 608.01(p).

The following formulas represent the novel 4-oxa phenyl-substituted prostaglandin analogs of this invention: ##STR1## Formulas XII, XIV, XVI, and XVIII represent 4-oxa phenyl-substituted compounds of the PGE type.

In those formulas, R₁ is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo. R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are hydrogen or alkyl of one to 4 carbon atoms, inclusive. The divalent moiety --C_(n) H_(2n) -- represents alkylene of one to 10 carbon atoms, inclusive, with one to 5 carbon atoms, inclusive, between --CHR₂ -- and --O--. The divalent moiety --C_(m) H_(2m) -- represents alkylene of one to 9 carbon atoms, inclusive, with one to 4 carbon atoms, inclusive, between --CHR₂ -- and --O--. The divalent moiety --C_(p) H_(2p) -- represents alkylene of one to 8 carbon atoms, inclusive, with one, 2, or 3 carbon atoms between --CH=CH-- or --C.tbd.C-- and --O--. The divalent moiety --C_(q) H_(2q) -- represents alkylene of one to 7 carbon atoms, inclusive, with 1 or 2 carbon atoms between --CH=CH-- or --C.tbd.C-- and --O--. The moiety --C_(t) H_(2t) -- represents a valence bond, i.e., wherein t is zero, or alkylene of one to 10 carbon atoms, inclusive, i.e., wherein t is one to 10, substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms, inclusive, between --CR₃ OH-- and the ring. When one or 2 fluoro are present as substituents of --C_(t) H_(2t) --, that moiety will contain 2t- 1 or 2t-2 hydrogen atoms, respectively, rather than 2t hydrogen atoms. The symbol T represents alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉ is hydrogen, alkyl of one to 4 carbon atoms inclusive, or tetrahydropyranyl. The symbol s represents zero, one, 2 or 3. Regarding the combination (T)_(s) attached to the phenyl ring, no more than two T are other than alkyl. Except for that proviso, when two or three T are present as substituents, they are the same or different.

The wavy line ˜ in formulas XII, XIV, XVI, and XVIII indicates attachment of the group to the ring in alpha or beta configuration.

Formulas XII, XIV, XVI, and XVIII include lower alkanoates, and also pharmacologically acceptable salts when R₁ is hydrogen.

Also included in Formulas XII, XIV, XVI, and XVIII are separate isomers wherein the side chain hydroxy is in S or R (epi) configuration.

Included in Formula XIV, are both the cis and the trans compounds with respect to the carbon-carbon double bond in the carboxy-terminated side chain. In all of the compounds containing --CH=CR₄ --, that carbon-carbon double bond is in trans configuration, and the chain containing R₄ is attached to the cyclopentane ring in beta configuration in compounds encompassed by Formulas XII, XIV, XVI, and XVIII.

The novel 4-oxa phenyl-substituted prostaglandin analogs of this invention include racemic compounds and both optically active enantiomeric forms thereof. As discussed hereinabove, two structural formulas are required to define accurately these racemic compounds. For convenience, only a single structural formula is used, for example, Formulas XII, XIV, XVI, and XVIII, to define the racemic form and both enantiomeric forms of each group of novel prostaglandin analogs. Each formula is, however, to be construed as including said racemic forms and both of said optically active enantiomeric forms. 

I claim:
 1. A compound of the formula: ##STR2## wherein R₁ is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2 or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo; wherein R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein C_(m) H_(2m) is alkylene of one to 9 carbon atoms, inclusive, with one to 4 carbon atoms, inclusive, between --CHR₂ -- and --O--; wherein C_(t) H_(2t) represents (1) a valence bond or (2) alkylene of one to 10 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms, inclusive, between --CR₃ OH-- and the ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or tetrahydropyranyl, and s is zero, one, 2, or 3, with the proviso that no more than two T are other than alkyl; and wherein ˜ indicates attachment of the group to the ring in alpha or beta configuration; including the lower alkanoates thereof, and the pharmacologically acceptable salts thereof when R₁ is hydrogen.
 2. A compound according to claim 1 wherein ##STR3## is

    --(CH.sub.2).sub.3 --O--(CH.sub.2).sub.2 COOR.sub.1

wherein R₁ is as defined in claim
 1. 3. A compound according to claim 2 wherein C_(t) H_(2t) is straight chain alkylene of one to 4 carbon atoms with or without a fluoro or alkyl substituent on the carbon atom adjacent to the hydroxy-substituted carbon atom.
 4. A compound according to claim 3 wherein the side chain hydroxy is in S configuration.
 5. A compound according to claim 4 wherein R₄ is hydrogen.
 6. A compound according to claim 5 wherein R₃ is hydrogen.
 7. A compound according to claim 6 wherein C_(t) H_(2t) is (CH₂)_(d) wherein d is one, 2, 3, or
 4. 8. A compound according to claim 7 wherein d is
 2. 9. 4-Oxa-17-phenyl-18,19,20-trinor-PGE₁, a compound according to claim
 8. 10. 4-Oxa-17-phenyl-18,19,20-trinor-PGE₁, ethyl ester, a compound according to claim
 8. 11. A compound according to claim 5 wherein R₃ is methyl.
 12. A compound according to claim 11 wherein C_(t) H_(2t) is (CH₂)_(d) wherein d is one, 2, 3, or
 4. 13. A compound according to claim 12 wherein d is
 2. 14. 4-Oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, a compound according to claim
 13. 15. 4-Oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, ethyl ester, a compound according to claim
 13. 16. A compound according to claim 3 wherein the side chain hydroxy is in R (epi) configuration.
 17. A compound according to claim 16 wherein R₄ is hydrogen.
 18. A compound according to claim 17 wherein R₃ is methyl.
 19. A compound according to claim 18 wherein C_(t) H_(2t) is (CH₂)_(d) wherein d is one, 2, 3, or
 4. 20. A compound according to claim 19 wherein d is
 2. 21. 15-Epi-4-oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, a compound according to claim
 20. 22. 15-Epi-4-oxa-15-methyl-17-phenyl-18,19,20-trinor-PGE₁, ethyl ester, a compound according to claim
 20. 23. A compound of the formula: ##STR4## wherein R₁ is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo; wherein R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein C_(q) H_(2q) is alkylene of one to 7 carbon atoms, inclusive, with one or 2 carbon atoms between --CH=CH-- and --O--; wherein C_(t) H_(2t) represents (1) a valence bond or (2) alkylene of one to 10 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms, inclusive, between --CR₃ OH-- and the ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or tetrahydropyranyl, and s is zero, one, 2, or 3, with the proviso that no more than two T are other than alkyl; and wherein ˜ indicates attachment of the group to the ring in alpha or beta configuration; including the lower alkanoates thereof, and the pharmacologically acceptable salts thereof when R₁ is hydrogen.
 24. A compound according to claim 23 wherein ##STR5## is

    --CH.sub.2 --CH=CH--CH.sub.2 --O--(CH.sub.2).sub.2 --COOR.sub.1,

wherein R₁ is as defined in claim
 23. 25. A compound of the formula: ##STR6## wherein R₁ is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted witih one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo; wherein R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein C_(q) H_(2q) is alkylene of one to 7 carbon atoms, inclusive, with one or 2 carbon atoms between --C.tbd.C-- and --O--; wherein C_(t) H_(2t) represents (1) a valence bond or (2) alkylene of one to 10 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms, inclusive, between --CR₃ OH-- and the ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or tetrahydropyranyl, and s is zero, one, 2, or 3, with the proviso that no more than two T are other than alkyl; and wherein ˜ indicates attachment of the group to the ring in alpha or beta configuration; including the lower alkanoates thereof, and the pharmacologically acceptable salts thereof when R₁ is hydrogen.
 26. A compound according to claim 25 wherein ##STR7## is

    --CH.sub.2 --C.tbd.C--CH.sub.2 --O--(CH.sub.2).sub.2 --COOR.sub.1

wherein R₁ is as defined in claim
 25. 27. A compound of the formula: ##STR8## wherein R₁ is hydrogen, alkyl of one to 8 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the β-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo; wherein R₂, R₃, R₄, R₅, R₆, R₇, and R₈ are hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein C_(m) H_(2m) is alkylene of one to 9 carbon atoms, inclusive, with one to 4 carbon atoms, inclusive, between --CHR₂ -- and --O--; wherein C_(t) H_(2t) represents (1) a valence bond or (2) alkylene of one to 10 carbon atoms, inclusive, substituted with zero, one, or 2 fluoro, with one to 7 carbon atoms, inclusive, between --CR₃ OH-- and the ring; wherein T is alkyl of one to 4 carbon atoms, inclusive, fluoro, chloro, trifluoromethyl, or --OR₉, wherein R₉ is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or tetrahydropyranyl, and s is zero, one, 2, or 3, with the proviso that no more than two T are other than alkyl; and wherein ˜ indicates attachment of the group to the ring in alpha or beta configuration; including the lower alkanoates thereof, and the pharmacologically acceptable salts thereof when R₁ is hydrogen.
 28. A compound according to claim 27 wherein ##STR9## is

    --(CH.sub.2).sub.3 --O--(CH.sub.2).sub.2 --COOR.sub.1,

wherein R₁ is as defined in claim
 27. 